Lithocholic bile acid selectively kills neuroblastoma cells, while sparing normal neuronal cells


Lithocholic bile acid selectively kills neuroblastoma cells, while sparing normal neuronal cells

Goldberg, Alexander A. and Beach, Adam and Davies, Gerald F. and Harkness, Troy A. A. and LeBlanc, André and Titorenko, Vladimir I. (2011) Lithocholic bile acid selectively kills neuroblastoma cells, while sparing normal neuronal cells. Oncotarget . ISSN 1949-2553

PDF - Published Version

Official URL:


Aging is one of the major risk factors of cancer. The onset of cancer can be postponed by pharmacological and dietary anti-aging interventions. We recently found in yeast cellular models of aging that lithocholic acid (LCA) extends longevity. Here we show that, at concentrations that are not cytotoxic to primary cultures of human neurons, LCA kills the neuroblastoma (NB) cell lines BE(2)-m17, SK-n-SH, SK-n-MCIXC and Lan-1. In BE(2)-m17, SK-n-SH and SK-n-MCIXC cells, the LCA anti-tumor effect is due to apoptotic cell death. In contrast, the LCA-triggered death of Lan-1 cells is not caused by apoptosis. While low concentrations of LCA sensitize BE(2)-m17 and SK-n-MCIXC cells to hydrogen peroxide-induced apoptotic cell death controlled by mitochondria, these LCA concentrations make primary cultures of human neurons resistant to such a form of cell death. LCA kills BE(2)-m17 and SK-n-MCIXC cell lines by triggering not only the intrinsic (mitochondrial) apoptotic cell death pathway driven by mitochondrial outer membrane permeabilization and initiator caspase-9 activation, but also the extrinsic (death receptor) pathway of apoptosis involving activation of the initiator caspase-8. Based on these data, we propose a mechanism underlying a potent and selective anti-tumor effect of LCA in cultured human NB cells. Moreover, our finding that LCA kills cultured human breast cancer and rat glioma cells implies that it has a broad anti-tumor effect on cancer cells derived from different tissues and organisms.

Divisions:Concordia University > Faculty of Arts and Science > Biology
Item Type:Article
Authors:Goldberg, Alexander A. and Beach, Adam and Davies, Gerald F. and Harkness, Troy A. A. and LeBlanc, André and Titorenko, Vladimir I.
Journal or Publication:Oncotarget
Date:11 October 2011
ID Code:36018
Deposited On:16 Oct 2011 13:41
Last Modified:16 Oct 2011 13:41
1. Boland CR, Ricciardiello L. How many mutations does it take to make a tumor? Proc Natl Acad Sci USA. 1999; 96: 14675-14677.

2. Karakosta A, Golias C, Charalabopoulos A, Peschos D, Batistatou A, Charalabopoulos K. Genetic models of human cancer as a multistep process. Paradigm models of colorectal cancer, breast cancer, and chronic myelogenous and acute lymphoblastic leukaemia. J Exp Clin Cancer Res. 2005; 24: 505-514.

3. Weinberg RA. (2007). The Biology of Cancer (New York: Garland Science, Taylor and Francis Group, LLC).

4. Blagosklonny MV. Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition. Cell Cycle. 2006; 5: 2087-2102.

5. Finkel T, Serrano M, Blasco MA. The common biology of cancer and ageing. Nature. 2007; 448: 767-774.

6. Blagosklonny MV. Validation of anti-aging drugs by treating age-related diseases. Aging. 2009; 1: 281-288.

7. Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Antoch MP, Blagosklonny MV. Rapamycin extends maximal lifespan in cancer-prone mice. Am J Pathol. 2010; 176: 2092-2097.

8. Collado M, Blasco MA, Serrano M. Cellular senescence in cancer and aging. Cell. 2007; 130: 223-233.

9. Serrano M, Blasco MA. Cancer and ageing: convergent and divergent mechanisms. Nat Rev Mol Cell Biol. 2007; 8: 715-722.

10. Inoki K, Corradetti MN, Guan KL. Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet. 2005; 37: 19-24.

11. Cully M, You H, Levine AJ, Mak TW. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer. 2006; 6: 184-192.

12. Harikumar KB, Aggarwal BB. Resveratrol: a multitargeted agent for age-associated chronic diseases. Cell Cycle. 2008; 7: 1020-1035.

13. Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 2009; 9: 563-575.

14. Shaw RJ. LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol. 2009; 196: 65-80.

15. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008; 132: 27-42.

16. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. (2008). Autophagy fights disease through cellular self-digestion. Nature. 2008; 451: 1069-1075.

17. Brech A, Ahlquist T, Lothe RA, Stenmark H. Autophagy in tumour suppression and promotion. Mol Oncol. 2009; 3: 366-375.

18. Eisenberg-Lerner A, Kimchi A. The paradox of autophagy and its implication in cancer etiology and therapy. Apoptosis. 2009; 14: 376-391.

19. Dalby KN, Tekedereli I, Lopez-Berestein G, Ozpolat B. Targeting the pro-death and pro-survival functions of autophagy as novel therapeutic strategies in cancer. Autophagy. 2010; 6: 322-329.

20. Kroemer G, Mariño G, Levine B. Autophagy and the integrated stress response. Mol. Cell. 2010; 40: 280-293.

21. Liang C, Jung JU. Autophagy genes as tumor suppressors. Curr Opin Cell Biol. 2010; 22: 226-233.

22. Turcotte S, Giaccia AJ. Targeting cancer cells through autophagy for anticancer therapy. Curr Opin Cell Biol. 2010; 22: 246-251.

23. Fleming A, Noda T, Yoshimori T, Rubinsztein DC. Chemical modulators of autophagy as biological probes and potential therapeutics. Nat Chem Biol. 2011; 7: 9-17.

24. Gottlieb E, Tomlinson IP. Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer. 2005; 5: 857-866.

25. King A, Selak MA, Gottlieb E. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene. 2006; 25: 4675-4682.

26. Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM. p53 regulates mitochondrial respiration. Science. 2006; 312:1650-1653.

27. Ma W, Sung HJ, Park JY, Matoba S, Hwang PM. A pivotal role for p53: balancing aerobic respiration and glycolysis. J Bioenerg Biomembr. 2007; 39: 243-246.

28. Goffrini P, Ercolino T, Panizza E, Giachè V, Cavone L, Chiarugi A, Dima V, Ferrero I, Mannelli M. Functional study in a yeast model of a novel succinate dehydrogenase subunit B gene germline missense mutation (C191Y) diagnosed in a patient affected by a glomus tumor. Hum Mol Genet. 2009; 18: 1860-1868.

29. Hao HX, Khalimonchuk O, Schraders M, Dephoure N, Bayley JP, Kunst H, Devilee P, Cremers CW, Schiffman JD, Bentz BG, Gygi SP, Winge DR, Kremer H, Rutter J. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science. 2009; 325: 1139-1142.

30. Kaelin WG. Jr. SDH5 mutations and familial paraganglioma: somewhere Warburg is smiling. Cancer Cell. 2009; 16: 180-182.

31. Bayley JP, Devilee P. Warburg tumours and the mechanisms of mitochondrial tumour suppressor genes. Barking up the right tree? Curr Opin Genet Dev. 2010; 20: 324-329.

32. Huber HJ, Dussmann H, Kilbride SM, Rehm M, Prehn JH. Glucose metabolism determines resistance of cancer cells to bioenergetic crisis after cytochrome-c release. Mol Syst Biol. 2011; 7: 470.

33. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011; 12: 21-35.

34. Hursting SD, Lavigne JA, Berrigan D, Perkins SN, Barrett JC. Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans. Annu Rev Med. 2003; 54: 131-152.

35. Mai V, Colbert LH, Berrigan D, Perkins SN, Pfeiffer R, Lavigne JA, Lanza E, Haines DC, Schatzkin A, Hursting SD. Calorie restriction and diet composition modulate spontaneous intestinal tumorigenesis in Apc(Min) mice through different mechanisms. Cancer Res. 2003; 63: 1752-1755.

36. Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM, Manola J, Brugarolas J, McDonnell TJ, Golub TR, Loda M, Lane HA, Sellers WR. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med. 2004; 10: 594-601.

37. Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, Kovalenko IG, Poroshina TE, Semenchenko AV, Provinciali M, Re F, Franceschi C. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol. 2005; 40: 685-693.

38. Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006; 5: 493-506.

39. Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 2006; 66: 10269-10273.

40. Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, Viollet B, Thompson CB. Systemic treatment with the anti-diabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 2007; 67: 6745-6752.

41. Shevah O, Laron Z. Patients with congenital deficiency of IGF-I seem protected from the development of malignancies: a preliminary report. Growth Horm IGF Res. 2007; 17: 54-57.

42. Algire C, Zakikhani M, Blouin MJ, Shuai JH, Pollak M. Metformin attenuates the stimulatory effect of a high-energy diet on in vivo LLC1 carcinoma growth. Endocr Relat Cancer. 2008; 15: 833-839.

43. Huang X, Wullschleger S, Shpiro N, McGuire VA, Sakamoto K, Woods YL, McBurnie W, Fleming S, Alessi DR. Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J. 2008; 412: 211-221.

44. Raffaghello L, Lee C, Safdie FM, Wei M, Madia F, Bianchi G, Longo VD. Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc Natl Acad Sci USA. 2008; 105: 8215-8220.

45. Zakikhani M, Dowling RJ, Sonenberg N, Pollak MN. The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase. Cancer Prev Res. 2008; 1: 369-375.

46. Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R. (2009). Caloric restriction delays disease onset and mortality in rhesus monkeys. Science. 2009; 325: 201-204.

47. Enns LC, Morton JF, Treuting PR, Emond MJ, Wolf NS, Dai DF, McKnight GS, Rabinovitch PS, Ladiges WC. Disruption of protein kinase A in mice enhances healthy aging. PLoS One. 2009; 4: e5963.

48. Goodwin PJ, Ligibel JA, Stambolic V. (2009). Metformin in Breast Cancer: Time for Action. J Clin Oncol. 2009; 27: 3271-3273.

49. Kalaany NY, Sabatini DM. Tumours with PI3K activation are resistant to dietary restriction. Nature. 2009; 458: 725-731.

50. Fontana L, Partridge L, Longo VD. Extending healthy life span - from yeast to humans. Science. 2010; 328: 321-326.

51. Hursting SD, Smith SM, Lashinger LM, Harvey AE, Perkins SN. Calories and carcinogenesis: lessons learned from 30 years of calorie restriction research. Carcinogenesis. 2010; 31: 83-89.

52. Longo VD, Fontana L. Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends Pharmacol Sci. 2010; 31: 89-98.

53. Campisi J. Cancer and ageing: rival demons? Nat Rev Cancer. 2003; 3: 339-349.

54. Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell. 2005; 120: 513-522.

55. Blasco MA. Telomere length, stem cells and aging. Nat Chem Biol. 2007; 3: 640-649.

56. Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007; 8: 729-740.

57. Rodier F, Campisi J, Bhaumik D. Two faces of p53: aging and tumor suppression. Nucleic Acids Res. 2007; 35: 7475-7484.

58. Sharpless NE, DePinho RA. How stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol. 2007; 8: 703-713.

59. Grimes A, Chandra SB. Significance of cellular senescence in aging and cancer. Cancer Res Treat. 2009; 41: 187-195.

60. Ohtani N, Mann DJ, Hara E. Cellular senescence: its role in tumor suppression and aging. Cancer Sci. 2009; 100: 792-797.

61. Kong Y, Cui H, Ramkumar C, Zhang H. Regulation of senescence in cancer and aging. J Aging Res. 2011; 2011: 963172.

62. Sharpless NE. Ink4a/Arf links senescence and aging. Exp Gerontol. 2004; 39: 1751-1759.

63. Pelicci PG. Do tumor-suppressive mechanisms contribute to organism aging by inducing stem cell senescence? J Clin Invest. 2004; 113: 4-7.

64. Sharpless NE, DePinho RA. Telomeres, stem cells, senescence, and cancer. J Clin Invest. 2004; 113: 160-168.

65. Vergel M, Marin JJ, Estevez P, Carnero A. Cellular senescence as a target in cancer control. J. Aging Res. 2011; 2011: 725365.

66. Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S, Pestell RG, Martinez-Outschoorn UE, Sotgia F, Lisanti MP. The reverse Warburg effect: Aerobic glycolysis in cancer-associated fibroblasts and the tumor stroma. Cell Cycle. 2009; 8: 3984-4001.

67. Lisanti MP, Martinez-Outschoorn UE, Chiavarina B, Pavlides S, Whitaker-Menezes D, Tsirigos A, Witkiewicz A, Lin Z, Balliet R, Howell A, Sotgia F. Understanding the “lethal” drivers of tumor-stroma co-evolution: emerging role(s) for hypoxia, oxidative stress and autophagy/mitophagy in the tumor microenvironment. Cancer Biol Ther. 2010; 10:537-542.

68. Martinez-Outschoorn UE, Balliet RM, Rivadeneira DB, Chiavarina B, Pavlides S, Wang C, Whitaker-Menezes D, Daumer KM, Lin Z, Witkiewicz AK, Flomenberg N, Howell A, Pestell RG, Knudsen ES, Sotgia F, Lisanti MP. Oxidative stress in cancer-associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells. Cell Cycle. 2010; 9: 3256-3276.

69. Martinez-Outschoorn UE, Pavlides S, Whitaker-Menezes D, Daumer KM, Milliman JN, Chiavarina B, Migneco G, Witkiewicz AK, Martinez-Cantarin MP, Flomenberg N, Howell A, Pestell RG, Lisanti MP, Sotgia F. Tumor cells induce the cancer-associated fibroblast phenotype via Caveolin-1 degradation: Implications for breast cancer and DCIS therapy with autophagy inhibitors. Cell Cycle. 2010; 9: 2423-2433.

70. Martinez-Outschoorn UE, Trimmer C, Lin Z, Whitaker-Menezes D, Chiavarina B, Zhou J, Wang C, Pavlides S, Martinez-Cantarin MP, Capozza F, Witkiewicz AK, Flomenberg N, Howell A, Pestell RG, Caro J, Lisanti MP, Sotgia F. Autophagy in cancer-associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFκB activation in the tumor stromal microenvironment. Cell Cycle. 2010; 9: 3515-3533.

71. Martinez-Outschoorn UE, Whitaker-Menezes D, Pavlides S, Chiavarina B, Bonuccelli G, Casey T, Tsirigos A, Migneco G, Witkiewicz A, Balliet R, Mercier I, Wang C, Flomenberg N, Howell A, Lin Z, Caro J, Pestell RG, Sotgia F, Lisanti MP. The autophagic tumor stroma model of cancer or “battery-operated tumor growth”: A simple solution to the autophagy paradox. Cell Cycle. 2010; 9: 4297-4306.

72. Pavlides S, Tsirigos A, Migneco G, Whitaker-Menezes D, Chiavarina B, Flomenberg N, Frank PG, Casimiro MC, Wang C, Pestell RG, Martinez-Outschoorn UE, Howell A, Sotgia F, Lisanti MP. The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism. Cell Cycle. 2010; 9: 3485-3505.

73. Pavlides S, Tsirigos A, Vera I, Flomenberg N, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S, Pestell RG, Martinez-Outschoorn UE, Sotgia F, Lisanti MP. Loss of Stromal Caveolin-1 leads to oxidative stress, mimics hypoxia and drives inflammation in the tumor microenvironment, conferring the “reverse Warburg effect”: A transcriptional informatics analysis with validation. Cell Cycle. 2010; 9: 2201-2219.

74. Pavlides S, Tsirigos A, Vera I, Flomenberg N, Frank PG, Casimiro MC, Wang C, Pestell RG, Martinez-Outschoorn UE, Howell A, Sotgia F, Lisanti MP. Transcriptional evidence for the “reverse Warburg effect” in human breast cancer tumor stroma and metastasis: similarities with oxidative stress, inflammation, Alzheimer disease and “neuron-glia metabolic coupling”. Aging. 2010; 2: 185-199.

75. Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S, Pestell RG, Martinez-Outschoorn UE, Sotgia F, Lisanti MP. The reverse Warburg effect: Aerobic glycolysis in cancer-associated fibroblasts and the tumor stroma. Cell Cycle. 2009; 8: 3984-4001.

76. Martinez-Outschoorn UE, Pavlides S, Howell A, Pestell RG, Tanowitz HB, Sotgia F, Lisanti MP. Stromal-epithelial metabolic coupling in cancer: Integrating autophagy and metabolism in the tumor microenvironment. Int J Biochem Cell Biol. 2011; 43: 1045-1051.

77. Lisanti MP, Martinez-Outschoorn UE, Pavlides S, Whitaker-Menezes D, Pestell RG, Howell A, Sotgia F. Accelerated aging in the tumor microenvironment: Connecting aging, inflammation and cancer metabolism with personalized medicine. Cell Cycle. 2011; in press.

78. Blagosklonny MV. Hypoxia-inducible factor: Achilles’ heel of antiangiogenic cancer therapy. Int J Oncol. 2001; 19: 257-262.

79. Blagosklonny MV. Antiangiogenic therapy and tumor progression. Cancer Cell. 2004; 5: 13-17.

80. White E, DiPaola RS. The double-edged sword of autophagy modulation in cancer. Clin Cancer Res. 2009; 15: 5308-5316.

81. Rabinowitz JD, White E. Autophagy and metabolism. Science. 2010; 330: 1344-1348.

82. White E, Karp C, Strohecker AM, Guo Y, Mathew R. Role of autophagy in suppression of inflammation and cancer. Curr Opin Cell Biol. 2010; 22: 212-217.

83. Chen N, Karantza V. Autophagy as a therapeutic target in cancer. Cancer Biol Ther. 2011; 11: 157-168.

84. Mathew R, White E. Autophagy in tumorigenesis and energy metabolism: friend by day, foe by night. Curr Opin Genet Dev. 2011; 21: 113-119.

85. Yang ZJ, Chee CE, Huang S, Sinicrope F. Autophagy modulation for cancer therapy. Cancer Biol Ther. 2011; 11: 169-176.

86. Goldberg AA, Richard VR, Kyryakov P, Bourque SD, Beach A, Burstein MT, Glebov A, Koupaki O, Boukh-Viner T, Gregg C, Juneau M, English AM, Thomas DY, Titorenko VI. Chemical genetic screen identifies lithocholic acid as an anti-aging compound that extends yeast chronological life span in a TOR-independent manner, by modulating housekeeping longevity assurance processes. Aging. 2010; 2: 393-414.

87. Longo VD, Kennedy BK
All items in Spectrum are protected by copyright, with all rights reserved. The use of items is governed by Spectrum's terms of access.

Repository Staff Only: item control page

Document Downloads

More statistics for this item...

Concordia University - Footer